Dabigatran Etexilate of formula (V), which chemically corresponds to the ethyl (E) 3-(2-((4-(N′-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate, is an anticoagulant from the class of direct thrombin inhibitors and is used for the treatment of thrombosis, cardiovascular diseases and similar diseases:

The active ingredient was first described in the patent application WO98/37075. In said document, a process for obtaining Dabigatran Etexilate according to the following route of synthesis is described:

In this process are required purification by chromatography in several of its steps, in particular, in the steps of obtaining the compound (III) and the amidine hydrochloride salt of formula (IV-HCl), which affects in a particularly disadvantageous way in the preparation of the compound of formula (V) on an industrial scale.
The first step corresponds to the preparation of the free base of the compound (III) by reacting the carboxylic acid (I) with the diamine (II) in the presence of a suitable coupling reagent. The reaction is carried out in tetrahydrofuran. The product obtained (III) requires a purification by chromatography, which is very difficult and costly to implement on an industrial scale.
In a next step the cyano derivative (III) is reacted with a dissolution of hydrogen chloride in ethanol, followed by the addition of ammonium carbonate in ethanol to give rise to the amidine hydrochloride salt (IV-HCl). Also in this case, it is required a purification by chromatography of the synthesis intermediate (IV-HCl).
The last step corresponds to the reaction of the intermediate (IV-HCl) with hexyl chloroformate to form the active pharmaceutical ingredient Dabigatran Etexilate.
In order to simplify the process for obtaining Dabigatran Etexilate described in WO98/37075, expensive and difficult to carry out on a large scale industry, several alternative processes have been developed.
In the patent application EP2262771A1 the compound of formula (III) is obtained in form of a salt with oxalic acid. This document indicates that the oxalate intermediate of the compound of formula (III) crystallizes easily and is a good synthesis intermediate to obtain the amidine hydrochloride salt of formula (IV-HCl) with high purity on an industrial scale. The compound of formula (III) in the form of oxalate is transformed in Dabigatran following the process of WO98/37075.
The patent EP2118090B1 protects a process for the preparation on an industrial scale of an synthesis intermediate product in the preparation of Dabigatran Etexilate, in particular, the amidine of formula (IV-pTsOH) which is isolated from the reaction medium by crystallization from a salt with p-toluenesulfonic acid. This amidine salt (IV-pTsOH) is obtained from a compound of formula (III) which is also isolated in form of a salt, in this case hydrobromide (III-HBr). Said patent explains that this salt (III-HBr) can be easily isolated, which significantly simplifies the process of preparation of this intermediate product in the case of reactions on an industrial scale.
The document WO2012/004396 explains that, following the processes described so far in the state of the art such as for example in WO98/37075, the step of preparation of the amidine of formula (IV) is particularly complicated. This step requires the use of large amounts of ammonia or ammonium carbonate required for the conversion of the compound of formula (III) into the amidine of formula (IV) and also to neutralize the large amount of acid still in dissolution. As a result, the process generates large amounts of residual salts in form of ammonium chloride. These secondary reaction products greatly complicate the process, especially on an industrial scale where chromatographies cannot be carried out. WO2012/004396 intends to solve said problem through the isolation of the imidate intermediate (VI) which is formed after the reaction of the compound of formula (III) with hydrogen chloride in ethanol:

In the bibliographic article “Intermediates of N-(2-(4-(N-Hexyloxycarbonyl)amidino)phenylaminomethyl)-1-methyl-1H-benzimidazol-5-ylcarbonyl)-(2-pyridil)beta-alanine ethyl ester” (IP.com Journal, 2009, vol. 9(3A), pp. 20; IPCOM000179673D) it is described a process for the preparation of the amidine hydrochloride salt of formula (IV-HCl) by reaction of the compound (III) with hydrogen chloride in ethanol, followed by a neutralization of anhydrous reaction medium with ammonium carbonate, inevitably generating, as in WO98/37075, huge amounts of ammonium chloride salts difficult to separate from the reaction mixture. Alternatively to the purification by chromatography proposed in WO98/37075, in this publication the purification step of the amidine hydrochloride salt (IV-HCl) consists of hot dissolving the crude reaction product in isopropanol and filtering while it is hot to remove the ammonium chloride salts. In a disadvantageous way, the same operation must be repeated several times to remove all salts and isolate the pure amidine hydrochloride salt (IV-HCl), resulting in a yield of the process of only 41%.
In document WO2010/045900, in the same way that in the document EP2262771A1 mentioned above, the amidine hydrochloride salt of formula (IV-HCl) is prepared from the oxalate salt of the compound of formula (III) by reacting with hydrogen chloride in ethanol, followed by reaction with ammonium carbonate in anhydrous. As described in WO2010/045900, the use of the oxalate salt of the compound of formula (III) as a starting material, allowed them to solve the problems encountered in the process proposed in WO98/37075. The inventors of WO2010/045900 reproduced the process according to WO98/37075 obtaining the amidine of formula (IV-HCl) in form of an oily substance with a high content of impurities, which had to be purified by chromatography as indicated in WO98/37075, since they failed to find any solvent for purifying the amidine by simple crystallization. For this reason, the inventors of WO2010/045900 sought other alternative process, in particular, through the oxalate salt of the compound of formula (III) to avoid a chromatography technically impossible to carry out on a large scale industrial.
In view of the foregoing, it is of great interest to continue investigating and develop other alternative simplified processes for the large scale industrial production of the active pharmaceutical ingredient Dabigatran Etexilate or salts thereof, avoiding purifications very complicated and costly in each step of preparation of synthesis intermediates, while maintaining a high quality of synthesis intermediates and improving yields of each step of reaction.